In vivo, cells exist in a context that includes other cells, extracellular matrix (ECM), growth factors and hormones. Cells must sense their relationship to other cells and the ECM, during morphogenesis and controlled tissue growth and repair. ECM mediates cell adhesion and cytoskeletal organization. and provides signals to cells that regulate cell growth and gene expression. These signals are mediated by specific cell surface receptors known as integrins. Many integrins are receptors for fibronectins (FNs), which are major components of the ECM. In vitro, FNs function in cell adhesion and migration, and have been implicated in many aspects of development, and hemostasis and tissue repair. Several disease states, including inflammation, thrombosis and metastasis of tumor cells, are associated with changes in cell adhesion and in expression of FNs. FNs are generated from a single gene by alternative RNA splicing. Specific changes in FN splice variant expression have been correlated with liver fibrogenesis, cutaneous wound healing, atherosclerosis, hypertension and vascular injury. Alternative exon EIIIA has recently been shown to have biological function in liver fibrogenesis, mediating the conversion of lipocytes to myofibroblasts. Regulation of exon EIIIA also occurs during development of cartilage and blood vessels. Thus our working hypothesis is that FNs affect specific cell types differently, and the basis for these differences is at least partly encoded by the alternative exons in FNs. In support of this hypothesis, we have found that a mouse strain lacking all FNs (FN.null) generated by the applicant by gene targeting, is embryonic lethal and diverse cell types require FNs for distinct functions during embryonic development. Our overall objective is to determine, in vivo, if FN splice variants play a significant role in the functions of FNs during development and disease. The primary goals are: 1) To determine the underlying mechanisms of defects in FN.null embryos. 2) To characterize an animal model in mice that aberrantly excludes the EIIIA domain in all FNs, concerning embryonic development, adult physiology and incidence of disease. 3) To characterize a complementary animal model in mice that aberrantly includes the EIIIA domain in all FNs.